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 Blood, 1 July 2008, Vol. 112, No. 1, pp. 150-158.
Prepublished online as a Blood First Edition Paper on April 30, 2008; DOI 10.1182/blood-2007-12-129395.

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NEOPLASIA

SDF-1/CXCR4 and VLA-4 interaction regulates homing in Waldenstrom macroglobulinemia

Hai T. Ngo1, Xavier Leleu1, Jack Lee2, Xiaoying Jia1, Molly Melhem1, Judith Runnels1,3, Anne-Sophie Moreau1, Nicholas Burwick1, Abdel Kareem Azab1, Aldo Roccaro1, Feda Azab1, Antonio Sacco1, Mena Farag1, Robert Sackstein2, and Irene M. Ghobrial1

1 Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA; 2 Harvard Skin Disease Research Center and the Department of Dermatology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA; and 3 Advanced Microscopy Core, Wellman Center for Photomedicine, Massachusetts General Hospital, Boston

Waldenstrom macroglobulinemia (WM) is characterized by widespread involvement of the bone marrow at the time of diagnosis, implying continuous homing of WM cells into the marrow. The mechanisms by which trafficking of the malignant cells into the bone marrow has not been previously elucidated. In this study, we show that WM cells express high levels of chemokine and adhesion receptors, including CXCR4 and VLA-4. We showed that CXCR4 was essential for the migration and trans-endothelial migration of WM cells under static and dynamic shear flow conditions, with significant inhibition of migration using CXCR4 knockdown or the CXCR4 inhibitor AMD3100. Similarly, CXCR4 or VLA-4 inhibition led to significant inhibition of adhesion to fibronectin, stromal cells, and endothelial cells. Decreased adhesion of WM cells to stromal cells by AMD3100 led to increased sensitivity of these cells to cytotoxicity by bortezomib. To further investigate the mechanisms of CXCR4-dependent adhesion, we showed that CXCR4 and VLA-4 directly interact in response to SDF-1, we further investigated downstream signaling pathways regulating migration and adhesion in WM. Together, these studies demonstrate that the CXCR4/SDF-1 axis interacts with VLA-4 in regulating migration and adhesion of WM cells in the bone marrow microenvironment.


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P. L. Bergsagel and W. M. Kuehl
WSU-WM and BCWM.1 should not be assumed to represent Waldenstrom macroglobulinemia cell lines
Blood, August 1, 2008; 112(3): 917 - 917.
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